Bone formation and degradation are tightly regulated by growth factor signaling between osteoblasts that are responsible for bone formation and osteoclasts that are responsible for bone re-absorption. Coupling bone formation by osteoblasts with degradation by osteoclasts has recently become a topic of intense study; with the list of growth factors identified as coupling factors expanding. Coupling bone formation with bone re-absorption requires the recruitment of osteoblasts and osteoclasts in parallel with the recruitment of their respective progenitor cells. Osteoblasts derive from mesenchymal stem cell (MSC) while osteoclasts derive from monocytes that are a part of the myeloid-lineage; however, it remains unknown how MSC or monocytes migrate from their niche in the bone marrow to sites of new bone formation. The current understanding of the spatial and temporal regulation of osteogenesis proposes that MSC migrate from their bone marrow niche to the endosteal surface; where the MSC differentiate into osteoblasts that produce new bone. In parallel, monocytes also migrate from their bone marrow niche to the endosteal surface; where they subsequently differentiate into osteoclasts that re-absorb bone. Growth factors known to regulate bone formation include TGFβ-, BMP- and the canonical Wnt-ligands. Osteoclast formation from monocyte precursors and bone re-absorption are regulated through the expression of MSCF, OPG and RANK-ligand. In parallel, osteoclast activity is also regulated by the expression of the TGFβ-, BMP- and the non-canonical Wnt-ligands. However, many developmental growth factors involved in tissue patterning, including TGFβ-, BMP- and the Wnt-ligands, promote bone formation and re-absorption. The maintenance of healthy bone requires constant remodeling, in which bone is made and destroyed continuously.
The introduction of an implant into bone results in a biochemical cascade that drives the pro-inflammatory response that is partially mediated by macrophage activity, which are derived from the myeloid lineage and can contribute to the degradation of bone or an implant material. Currently implants and implant materials are chosen to minimize the macrophage response while being optimally osteo-conductive and promoting maximum bone-implant integration. Alternatively, the introduction of autograft with an implant or the use of devitalized bone tissue graft (autograft) has been employed in concert with the material properties of an implant as a means of increasing osteo-integration; however, these approaches have often been problematic. Ideally, materials could be designed to be both self-organizing and self-assembling.
Generating bone as an adjuvant therapeutic approach employed during orthopedic trauma procedures or during routine spine fusion procedures represents a continuing challenge in orthopedic surgery. Specifically, these adjuvant bone-generating therapies seek to increase the growth of healthy bone at the site of surgical intervention in parallel with decreasing the healing time for bone. In the last several decades a number of attempts have been made to use various growth factors with osteogenic potential, including Bone Morphogenci Protein (BMP). Unfortunately, BMP based therapies intended to generate bone also carry a risk for tumorigenesis in patients, particularly those who may be undergoing X-radiation therapy or possess nascent undetected tumor. Further, BMP based therapies cannot be used in patients with active tumor, which is particularly unfortunate since these patients would benefit significantly from therapies that increase bone formation during surgical intervention.
Impaired fracture healing continues to present a significant challenge in orthopedic surgery and bone healing. Fracture non-union rates as high as 5-20% have been reported. The morbidity and cost associated with the treatment of patients developing non-unions can be substantial. Approximately 10% of the 6.2-million fractures encountered each year have difficulty healing. Various options exist to help accelerate bone healing, with unproven efficacy. Iliac crest bone graft is still considered to be the gold standard but has significant issues related to harvest site co-morbidity. Growth factor based therapies that include platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and parathyroid hormone (PTH) has shown initial success in cell culture studies; however, their efficacy remains unproven in clinical application. An additional option, such as bone morphogenic protein-2 (BMP2) and BMP7, has been shown to have success in accelerating fracture healing with diaphyseal fractures. However, there are risks associated with the use of BMP that include increased infection, increased risk of tumor growth, and an increased risk of local osteolysis. Many of the risks associated with treatments that include BMP also preclude the use of BMP for patients with other pathologies.
The therapeutic ability to increase bone formation, as an adjuvant during orthopedic surgery, while not increasing the potential for tumor growth is currently a limitation of commercially available biologics, when treating complex orthopedic problems such as spine fusion, fracture healing and the management of fracture non-unions.
In the field of orthopedic trauma, particularly with open fractures with large defects and non-unions; autogenous/allogenic bone grafts are the primary treatment options. However, autogenous harvested bone graft, used as the gold standard to achieve bone formation, has risks of infection and donor site pain. Other allogenic bone graft substitutes have shown poor healing when used singularly. The same limitations exist for spine surgeries when these graft options are used to achieve fusions.
Cortical and cancellous bone derived from cadaveric sources serves to fill space and is primarily osteo-conductive without significant osteo-inductive potential. Hence, biologics such as PDGF, VEGF and BMP are used to increase rates of healing or spine fusion, and their application adds to the cost of treatment. However, these biologic therapies stimulate proliferation during development in a range of cell phenotypes, which presents an inherent and unacceptable tumor risk.
De-mineralized bone matrix and calcium phosphate substitutes have not shown high efficacy at accelerated bone healing and also have significant cost associated with them due to production costs.
Recombinant BMP2 (rhBMP2) is an implant commercially developed by Medtronic known as INFUSE that is distributed in small (4.2-mg of BMP2 with 2× collagen sponges for a 15-mg/cm3 implant), medium (8.4-mg of BMP2 with 4× collagen sponges for a 15-mg/cm3 implant), large (12-mg of BMP2 with 6× collagen sponges for a 15-mg/cm3 implant) and large-II (12-mg of BMP2 with 1× collagen sponge for a 15-mg/cm3 implant). All sizes of the INFUSE implant are approved for spine and maxillofacial applications while only the large-II implant is approved for fracture. An INFUSE implant is administered by reconstituting the powdered BMP2 with sterile saline and then adding the BMP2-saline solution to the collagen sponge; after which the implant is delivered locally during surgical intervention.
Recombinant BMP7 (rhBMP7 or OP1) is an implant commercially developed by Stryker and now owned by Olympus known as OP1. OP1 implants are distributed as OP1-putty (20-mL vial containing powdered bovine cartilage and 3.3-mg of BMP7) or OP1-implant (1-g of powdered bovine cartilage and 3.3-mg of BMP7). The OP1-putty is approved for spine fusion surgeries while the OP1-implant is approved for treating fractures and fracture non-union surgery. The OP1-putty or the OP1-implant is administered by, reconstituting the powdered BMP7 with sterile saline first, and then adding the BMP7-saline solution to the collagen implant; after which the implant is delivered locally during surgical intervention.
The opioid growth factor-receptor (OGFR or ζ-opioid receptor) is a non-canonical, peri-nuclear opioid-receptor that does not share structural homology with the canonical μ-, κ- and δ-opioid-receptors (OPRM, OPRK and OPRD, respectively) and binds the native opioid-ligands less efficiently than the canonical opioid receptors. The opioid growth factor (OGF or met-5 enkephalin; met5) is the native ligand for the OGFR. Met5 is derived from the pro-hormone pro-enkephalin (PENK) and to a lesser extent pro-opiomelanocortin (POMC), which are first reduced by prohormone convertase (PCSK1 and PCSK2) and then carboxypeptidase E or D (CPE or CPD; enkephalin convertase) to form five copies of met5-enkephalin. Previous work identified met5 expression in osteoblasts and osteoprogenitors (Rosen et al., Proc Natl Acad Sci 88(9):3705-9, 1991; Rosen et al., J Bone Miner Res. 13(10):1515-20, 1998; Elhassan et al., J Bone and Miner Res., 13(1): 88-95, 1998; Cheng et al., Mol Biol Cell. 20(1):319-27, 2009). Additionally, Kuis et al. identified met5 in monocytes of the peripheral blood and spleen (Kuis et al., J Clin Invest. 88(3):817-24, 1991). Nevertheless, these investigators failed to identify a functional significance for OGFR-signaling in mesenchymal of myeloid lineages. Elhassan et al. (J Bone and Miner Res, 13(1): 88-95, 1998) discloses the presence of met5 in bone and joint tissues. However, there is no demonstrable link between met5 and bone formation.